This application is a 371 of PCT/FR95/07112 filed Dec. 21, 1995 which claims priority from french patent application No. 15501 filed Dec. 22, 1994.
The present invention relates to a unit galenical formulation of the soft capsule type, i.e. comprising firstly an outer envelope comprising gelatin and secondly a non-aqueous liquid or semi-liquid internal phase containing a spermicidal active principle in solution.
More particularly, the invention relates to a galenical formulation of this type for vaginal use as a local contraceptive and/or for combatting sexually-transmitted diseases and/or HIV.
At present, there exist numerous spermicidal substances in the form of vaginal suppositories, creams, cream- or solution-impregnated sponges, and tablets for local contraception. All spermicidal agents are naturally surface-active agents.
For example, U.S. Pat. No. 4,983,393 and U.S. Pat. No. 5,069,906 describe a solidified gel composition which dissolves in the presence of vaginal fluids, EP-A-0 587 431 describes a vaginal suppository which dissolves in the vagina, comprising a hydrosoluble lyophilized foam and a spermicide, and U.S. Pat. No. 4,187,286 describes a vaginal suppository comprising a mixture of polyethylene glycol, a spermicide, a thickening agent, a foaming agent, and alginic acid. EP-A-0 359 402 describes a contraceptive vaginal suppository having prolonged effect comprising a spermicide, a polymer gum, a dispersing agent, and as its major excipient, polyoxyethylene glycol (PEG), but that constitutes a homogeneous and solid galenical formulation of composition that could not be adapted to the internal phase of a soft capsule, given the highly hydrophilic nature of PEG which would spontaneously destroy the gelatin outer phase.
The xe2x80x9csoft capsulexe2x80x9d galenical formulation is well known, having an outer phase which is initially solid and thus easy to handle and put into place, comprising gelatin, in particular constituted by gelatin and glycerin, enclosing a liquid or semi-liquid internal phase containing a therapeutic agent.
For example, FR-A-2 372 635 describes a soft capsule whose internal phase is constituted for the most part by a surface-active agent, and which is thus incompatible with vaginal use for reasons of mucous membrane intolerance; EP-A-0 121 321 describes a soft capsule comprising an active principle which is dissolved or in suspension, and a composition preventing the soft capsule from becoming brittle.
Also, the development of sexually-transmitted diseases (STD) in recent years, and in particular infection by HIV, has led to an ever-increasing use of condoms.
However, it is recommended that use of a condom should be associated with use of an appropriate lubricating agent, i.e. one that does not degrade the mechanical strength properties of the condom and that does not increase its porosity due to the latex being attacked.
For example, EP-A-0 457 127 describes a lubricant based on silicone oil for treating the latex of condoms, EP-A-0 475 664 describes a lubricating composition and use thereof with condoms, and FR-A-2 666 587 describes a lubricant comprising polydimethylsiloxane.
It is also recommended, for greater security, to associate use of a condom with a spermicide (when the condom is used for contraceptive purposes) and/or with an agent that provides protection against sexually-transmitted infections (when the condom is used for protection against STD).
One of the objects of the invention is to propose a galenical formulation which satisfies these various requirements by means of a unit formulation for vaginal use, providing the known advantages of a soft capsule, presenting properties that are simultaneously spermicidal, antiseptic, and lubricating, and which is also reliably compatible with condoms, without any danger of damaging the rubber latex thereof.
According to bibliographic studies, a large number of vaginally-administered formulations (gels, vaginal suppositories, soft capsules, and the like) have the property of spoiling the physical characteristics of the rubber latex of condoms.
A major problem lies in the fact that the rubber latex of condoms loses its properties, and in particular its bursting strength, when it comes into contact with a large number of vaginally-administered formulations.
In addition, the galenical formulation must be well tolerated, stable, and galenically acceptable.
It must satisfy numerous requirements, and in particular:
it must provide bioadhesion to avoid as much as possible the phenomenon of outflow;
it must ensure that the vehicles are compatible with the active principle;
it must favor uniform mixing of the internal phase with vaginal secretions by being hydrophilic to some extent, while ensuring that its hydrophilic nature is compatible with the outer phase including the gelatin so as to avoid denaturing it (otherwise the capsule would melt on its own before being used); and
the ingredients selected must be compatible both with the outer phase and with the rubber latex of condoms.
The present invention solves all of the above-mentioned problems by proposing a unit galenical formulation of the above-specified type, characterized in that the active principle is constituted by a spermicide and in that the internal phase includes, in addition to the active principle: a major proportion of a lipophilic agent compatible with the rubber latex of a condom; a minor proportion of at least one hydrodispersible agent; at least one bioadhesion agent; and at least one agent for gelling the lipophilic agent.
According to various advantageous subsidiary characteristics:
the spermicide is selected from benzalkonium chloride, benzethonium chloride, cetyl pyridinium chloride, methylbenzethonium chloride, tetradecyltri-methyl ammonium bromide, benzalkonium bromide, monyl-phenyl ethers, lauryl ethers, and octoxynols, the spermicide is more particularly of cationic form, and advantageously benzalkonium chloride;
the lipophilic agent compatible with the rubber latex of a condom is a silicone oil;
the hydrodispersible agent is a non-ionic non-surface-active compound, preferably selected from the group comprising: esters of fatty acids and of polyols; lauric alcohol and polyethylene glycol ether; polyoxy-ethylene castor oil; polyoxyethylene glycerides; polyoxy-ethylene glycols; sucroglycerides of palm oils; and rectified ethyldiethyleneglycol; and advantageously a mixture of polyoxyethylene glycol and of 7-glyceryl-cocoate of polyoxyethylene glycol;
the bioadhesion agent is a biocompatible polymer, preferably selected from: carboxyvinyl acids; carboxy-methylcellulose; sodium carboxymethylcellulose; methyl-cellulose; hydroxypropylcellulose; hydroxypropylmethyl-cellulose; agar-agar; aluminum silicate; carrageenates; and carob gum; and more particularly hydroxypropyl-cellulose;
the agent for gelling the lipophilic agent is selected from the group comprising: silica; aluminum monostearate; aluminum tristearate; and cetyl alcohol; and more particularly silica; and
its internal phase compatible with the rubber latex of a condom satisfies the general formula: benzalkonium chloride, 50% solutionxe2x80x940.265 g to 2.65 g; silicaxe2x80x945 g to 7 g; hydroxypropylcellulosexe2x80x946 g to 8 g; 7-glyceryl-cocoate of polyoxyethylene glycolxe2x80x949 g to 11 g; polyoxyethylene glycol 400 xe2x80x944 g to 6 g; silicone oilxe2x80x94q.s. 100 g.
The invention also provides a method of obtaining a unit galenical formulation, the method being characterized in that it consists: a) in adding a solution of benzalkonium chloride to silicone oil while stirring; b) in incorporating polyoxyethylene glycol 400 and 7-glyceryl-cocoate of polyoxyethylene glycol in liquid form to the mixture a); c) in mixing the product b) for sufficient time to obtain good homogenization; d) in adding hydroxypropylcellulose to the product c); e) in mixing the product d); f) in incorporating the silica; and g) in stirring until the final product is obtained which is inserted into the envelope comprising gelatin.
Various advantages and characteristics of the present invention appear from the examples below.
In all of the examples of the present invention, mention is made of the content of the internal phase, it being understood that this phase is inserted into an outer envelope including gelatin, in particular an outer envelope of gelatin/glycerin known as a xe2x80x9csoft capsulexe2x80x9d.
Unless stated to the contrary, the examples are given for a quantity of 100 grams.